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Unlike macrophages, the hepatic parenchymal cells express cholesterol-7α-hydroxylase (CYP7A1) which regulates the conversion of cholesterol into bile acids, the major quantitative pathway maintaining cholesterol homeostasis. We examined if CYP7A1 expression in RAW 264.7 macrophages could prevent the accumulation of cholesterol when they were incubated with acetyl-LDL. A single cell clone (designated as 7αRAW cells) that stably expresses rat CYP7A1 displayed similar rates of growth as non-transfected RAW cells. The CYP7A1 enzymatic activity expressed by microsomes obtained from 7αRAW cells was similar to that expressed by microsomes obtained from mouse liver. Incubating non-transfected RAW with increasing amounts of acetyl-LDL caused a parallel accumulation of cholesterol, whereas 7αRAW cells displayed a complete resistance to cholesterol accumulation. 7αRAW cells displayed increased expression of both ABCA1 mRNA (3.1-fold, P < 0.001) and ABCG1 mRNA (2.2-fold, P < 0.01), whereas the expression of scavenger receptor class A mRNA was unchanged. 7 αRAW cells also displayed small but significant increases in the rate of efflux of [3H]cholesterol to both delipidated apolipoprotein A1 and to HDL. Thus, CYP7A1 expression in RAW cultured macrophages prevented the accumulation of cholesterol from acetyl-LDL via both increased metabolism and efflux of cholesterol.—Moore, G. L., and R. A. Davis. Expression of cholesterol-7 α-hydroxylase in murine macrophages prevents cholesterol loading by acetyl-LDL. J. Lipid Res. 2002. 43: 629–635.